Effects of radiation on normal tissues: Hypothetical mechanisms and limitations of in situ assays of clonogenicity

Abstract

It is argued that proliferating normal tissues fall into two categories. In type H (for hierarchical) tissues, cells either multiply or perform tissue-specific functions. Sterilizing doses or radiation immediately initiate a gradual depopulation of irreversibly postmitotic, mature cells. The constant rate of functional cell depletion is given by physiological longevity of the cells. Consequently the onset of maximal depopulation is dose-independent and, after a range of radiation doses, the peak of milder damage is seen earlier than that of a more severe one. In type F (for flexible) tissues all cells are assumed to have the potential for proliferation and are also engaged in tissue-specific functions. Radiation leads to dose-dependent loss of the functional cells through their mitotic death, both immediately after exposure and during the next phase of increased compensatory proliferation resulting in accelerated expression of radiation damage ('avalanche'). Consequently the more severe damage following larger doses of radiation is seen earlier than the milder one produced with smaller doses. Assays of cell clonogenicity in vivo concern almost exclusively type H populations. The large radiation/drug/heat doses administered in these assays serve both to dilute the clonogenic cells by at least two orders of magnitude, and to produce a measurable response. When comparing two agents or interpreting their combined action it is advisable to ensure that the dilution step yields qualitatively comparable samples of clonogenic cells to be then characterized in terms of dose-survival curve parameters.

A Mechanism of Intracellular Timing and its Cooperation with Extracellular Signals in Controlling Cell Proliferation and Differentiation, an Amended Hypothesis

“…This is essential whenever new cells are needed during growth and regeneration and a!ords, in turn, intracellular di!erentiation signals to stop proliferation again. Examples are the endo-and mesothelium, kidney parenchyma, hepatocytes, neuroglia, CONTROL OF CELL PROLIFERATION "brocytes (Michalowski, 1981), and vascular smooth muscle cells (Owens & Wise, 1997).…”

Effect of Radiotherapy on Peritoneal Function in Continuous Ambulatory Peritoneal Dialysis

“…The mechanisms behind the early effects are rela tively well understood [8], but this is not so for the late effects. However, it has been suggested that vascular dam age is the predominant factor leading to the development of late effects.…”

The role of cell differentiation in controlling cell multiplication and cancer

“…During forthcoming embryogenesis further intermediate steps of determination and diVerentiation lead to the development of a pedigree of cell types with terminally diVerentiated cells (Slack 1991). In the adult stage of mammals the processes of cell specialization continue in the cell renewal systems that exist both as a hierarchical type that contains true stem cells, and a Xexible type that does not contain stem cells (Michalowski 1981) and thus depends on dediVerentiation for cell renewal (Fig. 1).…”

“…The reason is that there are tissues the cells of which must perform specialized functions and still be able to proliferate if new cells are needed during the growth of the organism or when injured or worn cells must be replaced. In mammals this is known to occur in the so-called Xexible cell renewal systems such as in the endo-and mesothelium, liver and kidney parenchymal cells, Wbroblasts, neuroglia (Michalowski 1981), Schwann cells (Casella et al 2000) and vascular smooth muscle cells (Owens and Wise 1997). To execute specialized functions, these cells require cytoplasmic structures which are incompatible with proliferation and, thus, must be disassembled or dislocated before the cells are able to enter mitosis (Warren and Wickner 1996).…”